CA1205071A - Ketals of 3'"-dehydrocardenolide tridigitoxosides - Google Patents
Ketals of 3'"-dehydrocardenolide tridigitoxosidesInfo
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- CA1205071A CA1205071A CA000416391A CA416391A CA1205071A CA 1205071 A CA1205071 A CA 1205071A CA 000416391 A CA000416391 A CA 000416391A CA 416391 A CA416391 A CA 416391A CA 1205071 A CA1205071 A CA 1205071A
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Abstract
ABSTRACT
Ketals of 31'"-dehydrocardenolide tridigitoxosides The present invention provides ketals of 3"'-dehydrocardenolide tridigitoxosides of the general formula:- (I) in which R1 and R2 are identical alkyl radicals con-taining up to 3 carbon atoms or together represent a cyciic ketal containing 2 to 6 carbon atoms, represents two hydrogen atoms, the group or the radical wherein R1 and R2 have the above-given meaning, and R4 is a hydrogen atom or a lower acyl or alkyl radical.
The present invention also provides processes for the preparation of these ketals, as well as pharmaceutical compositions containing them, which are useful for the treatment of cardiac insufficiency.
Ketals of 31'"-dehydrocardenolide tridigitoxosides The present invention provides ketals of 3"'-dehydrocardenolide tridigitoxosides of the general formula:- (I) in which R1 and R2 are identical alkyl radicals con-taining up to 3 carbon atoms or together represent a cyciic ketal containing 2 to 6 carbon atoms, represents two hydrogen atoms, the group or the radical wherein R1 and R2 have the above-given meaning, and R4 is a hydrogen atom or a lower acyl or alkyl radical.
The present invention also provides processes for the preparation of these ketals, as well as pharmaceutical compositions containing them, which are useful for the treatment of cardiac insufficiency.
Description
07~
~ 1 The present invention is concerned with new ketals of 3"'-dehydrocardenolide tridigitoxosides, processes for the preparation thereof and pharma-ceutical composition~ containin~ them which are useful ~or the treatment of cardiac insufficiency.
The new ketal~ according to the present invention are compounds of the general formula -~3 Inl3 0,~
R OH OH ~I) O O
R~ R2 in which Rl and R2 are identical alkyl radicals con-taining up to 3 carbon atoms or tosether represent a cyclic ketal containing 2 ~o 6 carbon atoms, R3 represents two hydrogen atoms, the group ~ or the radical < 1 , wherein R1 and R2 hav~ the above-given meanings, and R4 is a hydrogen ato~ or a lower acyl or alkyl radical.
Acyl radicals are to be understood to be alkanoyl radicals containing up to 3 carbon atoms, the acetyl radical being preferred, and alkyl radicals are to ~e ~ 2 understood to be those containing up to 3 carbon atoms, the methyl radical being preferred~
The Diqitalis glycosides digîtoxin and digoxin mainly used in the therapy of heart insufficiency, as well as their derivatives, for example acetyl-digoxin and methyldigoxin, still leave something to be desired for the safety of their use: digoxin ar.d its derivative~ are preponderantly eliminated through the kidneys and can, therefore, lead to intoxications in the case of patients with impaired kidney function~
Digitoxin is the glycoside with the longest period o~
residence in the organism, for which ~eason possibly occurring intoxications, for example in the case of o~erdosing, can only subside again ext~emely ~lowly.
It has now been found that the ketals of 3~"-de-hydrocardenolide tridigitoxosides according to the pre-sent invention occupy an ideal middle position in that they are preponderantly eliminated extrarenally and thus, in the case of impaired kidney function, are less dangerous and, in addition, they are eliminated con-siderably more ~uickly then digitoxin, with elimination times being similar to that of digoxin.
The new compounds of general formula (I3 ean be prepared by reacting a compound of the general formula:-:~;20~
~0~0 R4 ~ ~U
in which R4 is hydrogen or a lower acyl or alkyl radical, and .
R5 represents two hydrogen atoms, the group or an oxygen atom, in per se known manner with a monohydroxy alkanol containing up to 3 carbon atoms or with a dihydroxy alkanol containing 2 to 6 carbon atoms, to give a ketal.
m e reaction is usually carried out in the alkanol in question as solvent, with the addition of , an acidic catalyst at a temperature of from ambient ¦
temperature to the boiling point of the solvent. Thereaction is promoted by a water-binding agent, pre~er-ably an orthoformic acid ester, or by a non-polar solvent which distils off azeotropically with water, for example, benzene or toluene.
itD7~
~ he novel compounds of formula (I) can also be obtained by acylating a compound of formula (I~, as defined above, in which R4 is a hydrogen atom, to produce a corresponding compound ~ formula (I) in which R4 is lower acyl.
Compounds obtained of formula (I3 can be converted to different compounds of formula (I), for example, the conversion of a compound of formula (I~
in which R4 is a hydrogen atom to a corresponding compound of formula (I) in which R4 is a lower acyl group.
It will be understood that when R5 is an oxygen atom, in the compound of formula (II), that sufficient alkanol is required to react with ~oth of the carbonyl groups which are to be converted to ketal groups.
The working up of the reaction mixture and purification of the end products takes place accord-ing to usual methods, including the use of chromato-graphic processes or by multiplicative partitioningand crystallisation.
5~
The identi.ty and purity of the compounds obtained were tested by thin layer chromatograms, using TLC finished plates (Merck silica gel 60/F 254, impregnation 2~/o formamide in acetone~ and developing with the elution agen~ heptane-methyl e~hyl ketone (1:1 vfv~ + 1.8% formamide or the elution agent xylene-methyl ethyl ketone ~2:3 v/v) + 5% formamide in Exa~ple G. The finished chromatograms were sprayed with trichloroacetic acid-chloramine reagent and the substances determined by their fluorescence in long-wave W ( ~ = 360 nm). The ru.nning paths (R3 in the chromatogram were, in each case, referred to a simult-aneously run standard~ RDt thereby signifies the R
value referred to the running path of 3l"-dehydro-digitoxin, ~ the R value referred to the running path of 3"',12-didehydrodigoxin and ~ g the R value referred to the running path of 31"-dehydrodigoxin.
The cardenolide glycosides according to the present invention can be administered 1 to 4 times .
daily in individual dosings of 0.05 - 1~0 mg~ Admin-istration is pxeferably orally but a parenteral administration can also be used.
The oral forms of administration are preferably tablets but hard capsules and soft gelatine capsules can also be used. For individual cases, for example for children, the preparation can be in the fonm of a liquid. For emergency and stationary treatmentj admirlistration can be by injection of appropriate solutions.
For the preparation of tablets or hard capsules for oral administration, the active material is mixed 5 with conventional adjuvants, such a~ lactose and starch, whereby, because of the small individual dose, the production of a pre-mixture is preferred. The active material-adjuvant mixture can be filled into hard capsules as a dry powder mass or, by granulation with binding agents, such as starch slurry or poly-vinylpyrrolidone, as granulate or, after further admixture of conventional breakdown agents and lubricants, pre~sed into tablet~.
Carrier materials for soft gelatine capsules can be the usual glycerol fatty acid ester~ but poly-ethyleneglycols can also ~e used as solvent ~or the active material. For a liquid or ampoule form, as solvent there can be used ethanol or polyhydroxy aloohols, optionally with ths addition of water and other conventional adjuvants.
The advantages of the compounds according to the present invention in comparison with digoxin and digitoxin, iOe. the compounds have a more rapid elim-ination with an increased rate of elimination via bile/faeces, is shown by the following experimental protocol:
~2~
~ 7 _ .
Groups of 4 cats each received an intravenous dose of 20 ~g./kg. of one of the glycosides mentioned in the following TableO The glycosides were marked with tritium by ~he method of Haberland and Maerten*
and the digoxin was marked with tritium by the method of Wartburg.**
The radioactivity was determined in the separately collected urine and faecal portions after 2 and 7 days.
The values summarised in the Table give the rate of elimination (column I) and the proportion of the elimination in the urin~ (column II)~
Column I gives the amount eliminated in th~ urine +
faeces after 2 days as a percentage of the total elimination after 7 days i Column II gives the percentage proportion of the elimination in the urine after 7 days, referred to the total elimination in urine faeces after 7 days~
_ __ glycoside I II
__ _ digoxin 53 44 digitoxin 20 16 _ 3~"-dehydrodigitoxin dimethylketal 48 27 3"'-dehydrodigitoxin ethyleneketal 43 24 . _ ~1 German Published Specification 19 59 064 Gerhard, Haberland, assigned to Beiresdorf ~G, July 7, 1977 ** Biochem. Pharmacol. 14, 1883 (1965) The following Examples are given for the purpo~e of illustrating the present invention:- ¦
~.
3~'-Dehydrodiqitoxin dimeth~lketal
~ 1 The present invention is concerned with new ketals of 3"'-dehydrocardenolide tridigitoxosides, processes for the preparation thereof and pharma-ceutical composition~ containin~ them which are useful ~or the treatment of cardiac insufficiency.
The new ketal~ according to the present invention are compounds of the general formula -~3 Inl3 0,~
R OH OH ~I) O O
R~ R2 in which Rl and R2 are identical alkyl radicals con-taining up to 3 carbon atoms or tosether represent a cyclic ketal containing 2 ~o 6 carbon atoms, R3 represents two hydrogen atoms, the group ~ or the radical < 1 , wherein R1 and R2 hav~ the above-given meanings, and R4 is a hydrogen ato~ or a lower acyl or alkyl radical.
Acyl radicals are to be understood to be alkanoyl radicals containing up to 3 carbon atoms, the acetyl radical being preferred, and alkyl radicals are to ~e ~ 2 understood to be those containing up to 3 carbon atoms, the methyl radical being preferred~
The Diqitalis glycosides digîtoxin and digoxin mainly used in the therapy of heart insufficiency, as well as their derivatives, for example acetyl-digoxin and methyldigoxin, still leave something to be desired for the safety of their use: digoxin ar.d its derivative~ are preponderantly eliminated through the kidneys and can, therefore, lead to intoxications in the case of patients with impaired kidney function~
Digitoxin is the glycoside with the longest period o~
residence in the organism, for which ~eason possibly occurring intoxications, for example in the case of o~erdosing, can only subside again ext~emely ~lowly.
It has now been found that the ketals of 3~"-de-hydrocardenolide tridigitoxosides according to the pre-sent invention occupy an ideal middle position in that they are preponderantly eliminated extrarenally and thus, in the case of impaired kidney function, are less dangerous and, in addition, they are eliminated con-siderably more ~uickly then digitoxin, with elimination times being similar to that of digoxin.
The new compounds of general formula (I3 ean be prepared by reacting a compound of the general formula:-:~;20~
~0~0 R4 ~ ~U
in which R4 is hydrogen or a lower acyl or alkyl radical, and .
R5 represents two hydrogen atoms, the group or an oxygen atom, in per se known manner with a monohydroxy alkanol containing up to 3 carbon atoms or with a dihydroxy alkanol containing 2 to 6 carbon atoms, to give a ketal.
m e reaction is usually carried out in the alkanol in question as solvent, with the addition of , an acidic catalyst at a temperature of from ambient ¦
temperature to the boiling point of the solvent. Thereaction is promoted by a water-binding agent, pre~er-ably an orthoformic acid ester, or by a non-polar solvent which distils off azeotropically with water, for example, benzene or toluene.
itD7~
~ he novel compounds of formula (I) can also be obtained by acylating a compound of formula (I~, as defined above, in which R4 is a hydrogen atom, to produce a corresponding compound ~ formula (I) in which R4 is lower acyl.
Compounds obtained of formula (I3 can be converted to different compounds of formula (I), for example, the conversion of a compound of formula (I~
in which R4 is a hydrogen atom to a corresponding compound of formula (I) in which R4 is a lower acyl group.
It will be understood that when R5 is an oxygen atom, in the compound of formula (II), that sufficient alkanol is required to react with ~oth of the carbonyl groups which are to be converted to ketal groups.
The working up of the reaction mixture and purification of the end products takes place accord-ing to usual methods, including the use of chromato-graphic processes or by multiplicative partitioningand crystallisation.
5~
The identi.ty and purity of the compounds obtained were tested by thin layer chromatograms, using TLC finished plates (Merck silica gel 60/F 254, impregnation 2~/o formamide in acetone~ and developing with the elution agen~ heptane-methyl e~hyl ketone (1:1 vfv~ + 1.8% formamide or the elution agent xylene-methyl ethyl ketone ~2:3 v/v) + 5% formamide in Exa~ple G. The finished chromatograms were sprayed with trichloroacetic acid-chloramine reagent and the substances determined by their fluorescence in long-wave W ( ~ = 360 nm). The ru.nning paths (R3 in the chromatogram were, in each case, referred to a simult-aneously run standard~ RDt thereby signifies the R
value referred to the running path of 3l"-dehydro-digitoxin, ~ the R value referred to the running path of 3"',12-didehydrodigoxin and ~ g the R value referred to the running path of 31"-dehydrodigoxin.
The cardenolide glycosides according to the present invention can be administered 1 to 4 times .
daily in individual dosings of 0.05 - 1~0 mg~ Admin-istration is pxeferably orally but a parenteral administration can also be used.
The oral forms of administration are preferably tablets but hard capsules and soft gelatine capsules can also be used. For individual cases, for example for children, the preparation can be in the fonm of a liquid. For emergency and stationary treatmentj admirlistration can be by injection of appropriate solutions.
For the preparation of tablets or hard capsules for oral administration, the active material is mixed 5 with conventional adjuvants, such a~ lactose and starch, whereby, because of the small individual dose, the production of a pre-mixture is preferred. The active material-adjuvant mixture can be filled into hard capsules as a dry powder mass or, by granulation with binding agents, such as starch slurry or poly-vinylpyrrolidone, as granulate or, after further admixture of conventional breakdown agents and lubricants, pre~sed into tablet~.
Carrier materials for soft gelatine capsules can be the usual glycerol fatty acid ester~ but poly-ethyleneglycols can also ~e used as solvent ~or the active material. For a liquid or ampoule form, as solvent there can be used ethanol or polyhydroxy aloohols, optionally with ths addition of water and other conventional adjuvants.
The advantages of the compounds according to the present invention in comparison with digoxin and digitoxin, iOe. the compounds have a more rapid elim-ination with an increased rate of elimination via bile/faeces, is shown by the following experimental protocol:
~2~
~ 7 _ .
Groups of 4 cats each received an intravenous dose of 20 ~g./kg. of one of the glycosides mentioned in the following TableO The glycosides were marked with tritium by ~he method of Haberland and Maerten*
and the digoxin was marked with tritium by the method of Wartburg.**
The radioactivity was determined in the separately collected urine and faecal portions after 2 and 7 days.
The values summarised in the Table give the rate of elimination (column I) and the proportion of the elimination in the urin~ (column II)~
Column I gives the amount eliminated in th~ urine +
faeces after 2 days as a percentage of the total elimination after 7 days i Column II gives the percentage proportion of the elimination in the urine after 7 days, referred to the total elimination in urine faeces after 7 days~
_ __ glycoside I II
__ _ digoxin 53 44 digitoxin 20 16 _ 3~"-dehydrodigitoxin dimethylketal 48 27 3"'-dehydrodigitoxin ethyleneketal 43 24 . _ ~1 German Published Specification 19 59 064 Gerhard, Haberland, assigned to Beiresdorf ~G, July 7, 1977 ** Biochem. Pharmacol. 14, 1883 (1965) The following Examples are given for the purpo~e of illustrating the present invention:- ¦
~.
3~'-Dehydrodiqitoxin dimeth~lketal
2 g. 3"'-Dehydrodigitoxin are dissolved in 40 ml.
anhydrous methylene chloride and 40 ml. methanol and, after the addition of 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid, the reaction mixture is left to stand for 1 day at ambient temper-ature, then diluted with 80 ml. 5% aqueous sodium bicarbonate solution, shaken out with chloroform and the chloroform phases are washed with water and evapox-ated in a vacuum. The crude product is separated with cyclohexane-ethyl acetate (2:1 v/v) over a cellulose column impregnated with formamide. The chromatographic-ally unifonm fractions give, after crystallisation from acetone, 640 m~. 3'l'-dehydrodigitoxin dimethylketal;
m.p- 206 - 210 C., RDt~ 1.96~
Example 2. !' ~
2 g. 3~"-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml~ absolute ethanol, mixed with 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid, left to stand for 2 days at ~5 ambient temperature and worked up as described in Example 1. The crude product is separated Wi~l heptane-methyl ethyl ketone (5~1 v/v) over a cellulose . . _ ~2~
g column impregnated with formamide. The chromato-graphically uniform fractions give, after crystallis-ation from acetone, 720 mg. 3"'-dehydrodigitoxin diethylketal, m.pO 189 - 193C.; RDt: 2.89.
2 g. 3"'-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml. ethylene glycol and, after the addition of 10 ml. triethyl orthoformate and 50 mg. p-toluenesulphonic acid, are reacted and worked up as described in Ex~nple 2. ~he crude product is fractionated with carbon tetrachloride-ethyl acetate (3:7 v/v + 2% water) over silica gel (+ ~/O water). l~e chromatographically uniform fractions yield, after crystallisation from acetone, 550 mg. 3"'-dehydrodigitoxin ethyleneketal, m.p.
152 - 156 C., RDt: 1.26-~- ' 2 g. 3"'-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml. propane-1,2-diol and mixed with 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid and reacted and worked up as described in Example 2. The crude product is separ-ated with cyclohexane-e~hyl acetate ~2:1 v/v) over a cellulose column impregnated with formamide. The chromatoyraphically uniform fractions give, after crystallisation from acetone, 630 mg. 3"'-dehydro-digitoxin propyleneketal mup. 159 - 163C., t: 1.68.
~ I
.,
anhydrous methylene chloride and 40 ml. methanol and, after the addition of 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid, the reaction mixture is left to stand for 1 day at ambient temper-ature, then diluted with 80 ml. 5% aqueous sodium bicarbonate solution, shaken out with chloroform and the chloroform phases are washed with water and evapox-ated in a vacuum. The crude product is separated with cyclohexane-ethyl acetate (2:1 v/v) over a cellulose column impregnated with formamide. The chromatographic-ally unifonm fractions give, after crystallisation from acetone, 640 m~. 3'l'-dehydrodigitoxin dimethylketal;
m.p- 206 - 210 C., RDt~ 1.96~
Example 2. !' ~
2 g. 3~"-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml~ absolute ethanol, mixed with 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid, left to stand for 2 days at ~5 ambient temperature and worked up as described in Example 1. The crude product is separated Wi~l heptane-methyl ethyl ketone (5~1 v/v) over a cellulose . . _ ~2~
g column impregnated with formamide. The chromato-graphically uniform fractions give, after crystallis-ation from acetone, 720 mg. 3"'-dehydrodigitoxin diethylketal, m.pO 189 - 193C.; RDt: 2.89.
2 g. 3"'-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml. ethylene glycol and, after the addition of 10 ml. triethyl orthoformate and 50 mg. p-toluenesulphonic acid, are reacted and worked up as described in Ex~nple 2. ~he crude product is fractionated with carbon tetrachloride-ethyl acetate (3:7 v/v + 2% water) over silica gel (+ ~/O water). l~e chromatographically uniform fractions yield, after crystallisation from acetone, 550 mg. 3"'-dehydrodigitoxin ethyleneketal, m.p.
152 - 156 C., RDt: 1.26-~- ' 2 g. 3"'-Dehydrodigitoxin are dissolved in 40 ml.
methylene chloride and 40 ml. propane-1,2-diol and mixed with 10 ml. triethyl orthoformate and 50 mg. ~-toluenesulphonic acid and reacted and worked up as described in Example 2. The crude product is separ-ated with cyclohexane-e~hyl acetate ~2:1 v/v) over a cellulose column impregnated with formamide. The chromatoyraphically uniform fractions give, after crystallisation from acetone, 630 mg. 3"'-dehydro-digitoxin propyleneketal mup. 159 - 163C., t: 1.68.
~ I
.,
3~ 2-Dideh 2 g. 3"',12-~idehydrodigoxin are dissolved in 40 ml. absolute ethanol and ~0 mlO methylene chloride and, after the addition of 10 ml. triethyl ortho~
fonmate and 50 mg. ~-toluenesulphonic acid, are left to stand for 1 day at ambient temperature. The reaction mixture is diluted wi~h 80 ml. 5% aqueous sodium bicarbonate solution, shaken out with 6 x 30 ml.
chlorofonm and the chloroform phases are washed with water and evaporated in a vacuum. The crude product is chromatographed over silica gel with cyclohexane and increasing amounts of ethyl acetate. Chromato-graphically unifonm fractions give, after crystallis-ation from acetone, 0.6 g. 3'l',12-didehydrodigoxin bis-~diethylketal); m.p. 190 - 195C.; ~ : 6Ø
~==~ 'I
1 g. 3"'~Dehydrodigoxin is dissolved in 20 ml.
anhydrous methylene chloride and 20 ml. methanol and, after the addition or 5 ml. triethyl orthoformate and 25 mg. ~-~toluenesulphonic acid, is reacted and worked up as described in Example 1. The crude product is separated with xylene-methyl ethyl ketone (3 1 v/v) ~2~
over a cellulose column impregnated with formamide.
The chromatographically unifonm fractions yield, after crystalli~a~ion from acetone-diethyl ether petroleum ether, 410 mg. 3"'-dehydrodigoxin dimethyl-ketal, m.p. 131 - 135C.; RDg 1.67.
~e~-
fonmate and 50 mg. ~-toluenesulphonic acid, are left to stand for 1 day at ambient temperature. The reaction mixture is diluted wi~h 80 ml. 5% aqueous sodium bicarbonate solution, shaken out with 6 x 30 ml.
chlorofonm and the chloroform phases are washed with water and evaporated in a vacuum. The crude product is chromatographed over silica gel with cyclohexane and increasing amounts of ethyl acetate. Chromato-graphically unifonm fractions give, after crystallis-ation from acetone, 0.6 g. 3'l',12-didehydrodigoxin bis-~diethylketal); m.p. 190 - 195C.; ~ : 6Ø
~==~ 'I
1 g. 3"'~Dehydrodigoxin is dissolved in 20 ml.
anhydrous methylene chloride and 20 ml. methanol and, after the addition or 5 ml. triethyl orthoformate and 25 mg. ~-~toluenesulphonic acid, is reacted and worked up as described in Example 1. The crude product is separated with xylene-methyl ethyl ketone (3 1 v/v) ~2~
over a cellulose column impregnated with formamide.
The chromatographically unifonm fractions yield, after crystalli~a~ion from acetone-diethyl ether petroleum ether, 410 mg. 3"'-dehydrodigoxin dimethyl-ketal, m.p. 131 - 135C.; RDg 1.67.
~e~-
4"'-Acetyl-3"'-dehydrodi~itoxin ethyleneketal 1 g. 3"'-Dehydrodigitoxin ethyleneketal is dissolved in 10 ml. dimethylformamide and, after the addition of 230 mg. triethylenediamine and 0.20 ml.
acetic anhydride, left to stand for 24 hours at ambient temperature. The reaction mixture is then diluted with 80 ml. water, shaken out with chloroform and the chloroform phases are evaporated in a vacuum.
The crude product is separated with heptane-methyl ethyl ketone (3:1 v/v) over a cellulose column impregnated with formamide. The chromatographically uniform fractions give, after crystallisation from acetone-diethyl ether, 510 mgO 4"'-acetyl-3"'-dehydrodigitoxin ethyleneketal; m.p. 239 - 243C., RDt: 2.68 1 g. 4"'-Methyl-3"'-dehydrodigitoxin is dis-solved in 20 ml. methylene chloride and 20 ml.
absolute ethanol~ mixed with 5 ml. triethyl ortho formate and 25 mg. ~-toluenesulphonic acid, left to stand for 2 days at ambient temperature and worked up as described in Example 1~ The crude product is separated with heptane-methyl ethyl ketone (4:1 v/v) over a cellulose column impregnated with formamide.
The chromatographically uniform fractions yield, after crystallisation from diethyl ether-petroleum ether~ 320 mg. 4"'-methyl-3"'-dehydrodigitoxin diethylketal; m.p~ 226 - 230C.; RDt: 4.68.
The 4"'-methyl-3"'-dehydrodigitoxin used a~
starting material is new and is prepared as follows:
6 g. Chromium trioxide are introduced at ambient temperature, while stirring, into a mixture of 8 ml.
pyridine and 150 ml. methylene chloride and the mixture is stirred for 15 minutes at ambient temper-ature. A solution of 8 g. 4"'-methyldigitoxin in 10 ml. pyridine and 100 ml. methylene chloride is slowly added thereto, the reaction mixture is stirred for lS minutes at ambient temperature, then heated to the boil under reflux for 1 hour, diluted with 500 ml~
water, ~haken out with chloroform and the chloroform phases are washed with a 5% aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulphate and evaporated in a vacuum. The crude pro-duct is separated with heptane-methyl ethyl ketone (2:1 v~v) over a cellulose column im~regnated with formamide. The chromatographically uniform fractions yield, after crystallisation`from chloroform-diethyl ~7~
ether, 4. 2 g. 4 "'-methyl-3 "'-dehydro~igitoxin: m.p.
213 - 217C.
acetic anhydride, left to stand for 24 hours at ambient temperature. The reaction mixture is then diluted with 80 ml. water, shaken out with chloroform and the chloroform phases are evaporated in a vacuum.
The crude product is separated with heptane-methyl ethyl ketone (3:1 v/v) over a cellulose column impregnated with formamide. The chromatographically uniform fractions give, after crystallisation from acetone-diethyl ether, 510 mgO 4"'-acetyl-3"'-dehydrodigitoxin ethyleneketal; m.p. 239 - 243C., RDt: 2.68 1 g. 4"'-Methyl-3"'-dehydrodigitoxin is dis-solved in 20 ml. methylene chloride and 20 ml.
absolute ethanol~ mixed with 5 ml. triethyl ortho formate and 25 mg. ~-toluenesulphonic acid, left to stand for 2 days at ambient temperature and worked up as described in Example 1~ The crude product is separated with heptane-methyl ethyl ketone (4:1 v/v) over a cellulose column impregnated with formamide.
The chromatographically uniform fractions yield, after crystallisation from diethyl ether-petroleum ether~ 320 mg. 4"'-methyl-3"'-dehydrodigitoxin diethylketal; m.p~ 226 - 230C.; RDt: 4.68.
The 4"'-methyl-3"'-dehydrodigitoxin used a~
starting material is new and is prepared as follows:
6 g. Chromium trioxide are introduced at ambient temperature, while stirring, into a mixture of 8 ml.
pyridine and 150 ml. methylene chloride and the mixture is stirred for 15 minutes at ambient temper-ature. A solution of 8 g. 4"'-methyldigitoxin in 10 ml. pyridine and 100 ml. methylene chloride is slowly added thereto, the reaction mixture is stirred for lS minutes at ambient temperature, then heated to the boil under reflux for 1 hour, diluted with 500 ml~
water, ~haken out with chloroform and the chloroform phases are washed with a 5% aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulphate and evaporated in a vacuum. The crude pro-duct is separated with heptane-methyl ethyl ketone (2:1 v~v) over a cellulose column im~regnated with formamide. The chromatographically uniform fractions yield, after crystallisation`from chloroform-diethyl ~7~
ether, 4. 2 g. 4 "'-methyl-3 "'-dehydro~igitoxin: m.p.
213 - 217C.
Claims (24)
1. A process for the preparation of a ketal of a 3'" dehydrocardenolide tridigitoxoside of the formula (I):- (I) in which R1 and R2 are identical alkyl radicals contain-ing up to 3 carbon atoms or together represent a cyclic ketal containing 2 to 6 carbon atoms, R3 represents two hydrogen atoms, the group or the radical wherein R1 and R2 are as defined above and R4 is a hydrogen atom or a lower acyl or alkyl radical, comprising:
a) reacting a compound of the formula (II):- (II) in which R5 represents two hydrogen atoms, the group or an oxygen atom and R4 is a hydrogen atom or a lower acyl or alkyl radical, with a monohydroxy alkanol containing up to 3 carbon atoms or a dihydroxy alkanol containing 2 to 6 carbon atoms, or b) acylating a compound of formula (I), as defined above, in which R4 is a hydrogen atom, to produce a corresponding compound of formula (I), in which R4 is a lower acyl radical, and, when desired, converting a compound obtained of formula (I), to a different compound of formula (I).
a) reacting a compound of the formula (II):- (II) in which R5 represents two hydrogen atoms, the group or an oxygen atom and R4 is a hydrogen atom or a lower acyl or alkyl radical, with a monohydroxy alkanol containing up to 3 carbon atoms or a dihydroxy alkanol containing 2 to 6 carbon atoms, or b) acylating a compound of formula (I), as defined above, in which R4 is a hydrogen atom, to produce a corresponding compound of formula (I), in which R4 is a lower acyl radical, and, when desired, converting a compound obtained of formula (I), to a different compound of formula (I).
2. A process according to claim 1a), comprising reacting said compound of formula (II) with said alkanol.
3. A process according to claim 1b), comprising acylating said compound of formula (I) in which R4 is a hydrogen atom.
4. A process according to claim 1a), including acylating a compound obtained of formula (I), in which R4 is a hydrogen atom.
5. A process according to claim 2, wherein said reacting is carried out with acid catalysis.
6. A process according to claim 2 or 5, wherein said reacting is carried out in the presence of a water binding or water-removing agent.
7. A process according to claim 2, for pre-paring 3 "'-dehydrodigitoxin dimethylketal, comprising reacting 3"'-dehydrodigitoxin with methanol.
8. A process according to claim 2, for pre-paring 3"'-dehydrodigitoxin diethylketal, comprising reacting 3"'-dehydrodigitoxin with ethanol.
9. A process according to claim 2, for pre-paring 3"'-dehydrodigitoxin ethyleneketal, comprising reacting 3"'-dehydrodigitoxin with ethylene glycol.
10. A process according to claim 2, for pre-paring 3'"-dehydrodigitoxin propyleneketal, comprising reacting 3'"-dehydrodigitoxin with propane-1,2-diol.
11. A process according to claim 2, for pre-paring 3'",12-didehydrodigoxin bis-(diethylketal), comprising reacting 3'",12-didehydrodigoxin with ethanol.
12. A process according to claim 2, for pre-paring 3'"-dehydrodigoxin dimethylketal, comprising reacting 3'"-dehydrodigoxin with methanol.
13. A process according to claim 3, for pre-paring 4'"-acetyl-3'"-dehydrodigitoxin ethyleneketal, comprising acetylating 3"'-dehydrodigitoxin ethylene-ketal.
14. A process according to claim 9, including the step of acetylating the 3"'-dehydrodigitoxin ethyleneketal to produce 4"'-acetyl-3 "'-dehydro-digitoxin ethyleneketal.
15. A process according to claim 2, for pre-paring 4'"-methyl-3'"-dehydrodigitoxin diethylketal, comprising reacting 4'"-methyl-3'"-dehydrodigitoxin with ethanol.
16. A ketal of a 3'"-dehydrocardenolide tri-digitoxoside of the formula (I):- (I) in which R1 and R2 are identical alkyl radicals con-taining up to 3 carbon atoms or together represent a cyclic ketal containing 2 to 6 carbon atoms, represents two hydrogen atoms, the group or the radical ,wherein R1 and R2 are as defined above, and R4 is a hydrogen atom or a lower acyl or alkyl radical, whenever prepared by the pro-cess of claim 1, 2 or 3, or by an obvious chemical equivalent.
17. 3 '"-Dehydrodigitoxin dimethylketal, when-ever prepared by the process of claim 7, or by an obvious chemical equivalent.
18. 3'" -Dehydrodigitoxin diethylketal, whenever prepared by the process of claim 8, or by an obvious chemical equivalent.
19. 3'"-Dehydrodigitoxin ethyleneketal, when-ever prepared by the process of claim 9, or by an obvious chemical equivalent.
20. 3'"-Dehydrodigitoxin propyleneketal, when-ever prepared by the process of claim 10, or by an obvious chemical equivalent.
21. 3'",12-Didehydrodigoxin bis-(diethylketal), whenever prepared by the process of claim 11, or by an obvious chemical equivalent.
22. 3'"-Dehydrodigoxin dimethylketal, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.
23. 4'"-Acetyl-3'"-dehydrodigitoxin ethylene-ketal, whenever prepared by the process of claim 13 or 14, or by an obvious chemical equivalent.
24. 4'"-Methyl-3'"-dehydrodigitoxin diethyl-ketal, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813146899 DE3146899A1 (en) | 1981-11-26 | 1981-11-26 | NEW KETALS OF 3 '' 'DEHYDRO CARDENOLIDE TRIDIGITOXOSIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DEP3146899.3 | 1981-11-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1205071A true CA1205071A (en) | 1986-05-27 |
Family
ID=6147267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000416391A Expired CA1205071A (en) | 1981-11-26 | 1982-11-25 | Ketals of 3'"-dehydrocardenolide tridigitoxosides |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4436735A (en) |
| EP (1) | EP0080675B1 (en) |
| JP (1) | JPS5892699A (en) |
| KR (1) | KR840002412A (en) |
| AT (1) | ATE12238T1 (en) |
| AU (1) | AU9075582A (en) |
| CA (1) | CA1205071A (en) |
| DD (1) | DD204928A5 (en) |
| DE (2) | DE3146899A1 (en) |
| DK (1) | DK523582A (en) |
| ES (1) | ES517673A0 (en) |
| FI (1) | FI824062L (en) |
| GR (1) | GR77738B (en) |
| HU (1) | HU185753B (en) |
| IL (1) | IL67324A0 (en) |
| PT (1) | PT75901B (en) |
| ZA (1) | ZA828642B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0530224A1 (en) * | 1990-05-07 | 1993-03-10 | The Board Of Regents Of The University Of Washington | Novel steroid glycosides useful in the early detection of hypertension |
| DE60218341D1 (en) * | 2001-12-14 | 2007-04-05 | Merck & Co Inc | NEW, SULTALINE DERIVATIVES ISOLATED FROM CULTURAL COMMENTS AND EFFECTS AS ANTIPOCULAR AGENTS |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE752284Q (en) * | 1969-08-11 | 1970-12-21 | Boehringer Mannheim Gmbh | Digoxine ethers having pharmaceutical prop- - erties |
| BE759912A (en) * | 1969-12-05 | 1971-06-04 | Boehringer Mannheim Gmbh | PERFECTED PROCESS FOR PREPARATION OF MONOMETHYL ETHERS DEDIGOXIN |
| DE2343400C3 (en) | 1973-08-29 | 1979-11-08 | Boehringer Mannheim Gmbh, 6800 Mannheim | Process for the 12 ß-hydroxylation of A-series digitalis glycosides |
| DE2354119A1 (en) | 1973-10-29 | 1975-05-15 | Boehringer Sohn Ingelheim | NEW ORTHOFORM DERIVATIVES OF DIGITOXIN, THE PROCESS FOR THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINED |
-
1981
- 1981-11-26 DE DE19813146899 patent/DE3146899A1/en not_active Withdrawn
-
1982
- 1982-11-05 US US06/439,653 patent/US4436735A/en not_active Expired - Fee Related
- 1982-11-19 AU AU90755/82A patent/AU9075582A/en not_active Abandoned
- 1982-11-19 GR GR69861A patent/GR77738B/el unknown
- 1982-11-20 DE DE8282110729T patent/DE3262707D1/en not_active Expired
- 1982-11-20 AT AT82110729T patent/ATE12238T1/en not_active IP Right Cessation
- 1982-11-20 EP EP82110729A patent/EP0080675B1/en not_active Expired
- 1982-11-22 KR KR1019820005259A patent/KR840002412A/en unknown
- 1982-11-22 JP JP57203836A patent/JPS5892699A/en active Pending
- 1982-11-22 IL IL67324A patent/IL67324A0/en unknown
- 1982-11-24 ZA ZA828642A patent/ZA828642B/en unknown
- 1982-11-24 DK DK523582A patent/DK523582A/en not_active Application Discontinuation
- 1982-11-25 HU HU823793A patent/HU185753B/en not_active IP Right Cessation
- 1982-11-25 FI FI824062A patent/FI824062L/en not_active Application Discontinuation
- 1982-11-25 ES ES517673A patent/ES517673A0/en active Granted
- 1982-11-25 CA CA000416391A patent/CA1205071A/en not_active Expired
- 1982-11-25 DD DD82245216A patent/DD204928A5/en unknown
- 1982-11-25 PT PT75901A patent/PT75901B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR840002412A (en) | 1984-07-02 |
| EP0080675A1 (en) | 1983-06-08 |
| FI824062L (en) | 1983-05-27 |
| DK523582A (en) | 1983-05-27 |
| GR77738B (en) | 1984-09-25 |
| ES8308890A1 (en) | 1983-08-16 |
| PT75901B (en) | 1985-10-04 |
| ATE12238T1 (en) | 1985-04-15 |
| EP0080675B1 (en) | 1985-03-20 |
| ES517673A0 (en) | 1983-08-16 |
| JPS5892699A (en) | 1983-06-02 |
| DD204928A5 (en) | 1983-12-14 |
| DE3146899A1 (en) | 1983-06-01 |
| FI824062A0 (en) | 1982-11-25 |
| HU185753B (en) | 1985-03-28 |
| US4436735A (en) | 1984-03-13 |
| IL67324A0 (en) | 1983-03-31 |
| AU9075582A (en) | 1983-06-02 |
| ZA828642B (en) | 1983-10-26 |
| PT75901A (en) | 1982-12-01 |
| DE3262707D1 (en) | 1985-04-25 |
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